- Email: [email protected]
Did the drug cause death? Codeine and breastfeeding
Comment
Institute of Infectious and Tropical Diseases, University of Brescia, I-25123 Brescia, Italy (CT); and Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA, USA (IF) [email protected] CT has served as adviser for, or has received lecture fees or grant support from, Abbott, Boehringer, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Pfizer, and Roche. IF has served as adviser for, or has received lecture fees or grant support from, Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, and Tibotec. 1
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Molina JM, Andrade-Villanueva J, Echevarria J, et al, for the CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48-week efficacy and safety results of the CASTLE study. Lancet 2008; 372: 646–55. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Jan 29, 2008. www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. pdf (accessed Aug 1, 2008). Clumeck N, Pozniak A, Raffi F, and the EACS Executive Committee. European AIDS Clinical Society (EACS) guidelines for the clinical management of HIV-infected adults. HIV Med 2008; 9: 65–71. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 2006; 296: 827–43. Eron J Jr, Yeni P, Gathe J Jr, et al, for the KLEAN study team. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 2006; 368: 476–82. Walmsley S, Ruxrungtham K, Slim J, et al. The Gemini Study: saquinavir (SQV/r) vs lopinavir/r (LPV/r) plus emtricitabine/tenofovir (FTC/TDF) as initial therapy in HIV-1 infected patients. 11th European AIDS Conference/EACS, Madrid, Spain; Oct 24–27, 2007: PS1/4 (abstr). Ortiz R, DeJesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 1389–97. Gathe J, da Silva B, Loutfy M. Study M05-730 primary efficacy results at week 48: phase 3, randomized, open-label study of lopinavir/ritonavir tablets once daily vs twice daily, co-administered with tenofovir df + emitricitabine in ARV-naive HIV-1-infected subjects. 15th Conference on Retrovirus and Opportunistic Infections, Boston, MA, USA; Feb 3–6, 2008: 775 (abstr).
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Rotger M, Taff P, Bleiber G, et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005; 192: 1381–86. Rodríguez-Nóvoa S, Martín-Carbonero L, Barreiro P, et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS 2007; 21: 41–46. Malan N, Krantz E, David N, et al. Efficacy and safety of atazanavir-based therapy in antiretroviral naïve subjects, both with and without ritonavir: 48-week results from AI424-089. 13th Conference on Retrovirus and Opportunistic Infections, Denver, CO, USA; Feb 5–8, 2006: 107LB (abstr). The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349: 1993–2003. Riddler SA, Haubrich R, DiRienzo G, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358: 2095–106. Markowitz M, Nguyen BY, Gotuzzo E, et al, for the Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46: 125–33. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: Week 48 results of the MERIT study. 4th IAS Conference on HIV Pathogenesis and Treatment and Prevention, Sydney, Australia; July 22–25, 2007: WESS104 (abstr). Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naïve patients. 14th Conference on Retrovirus and Opportunistic Infections (CROI), Los Angeles, CA, USA; Feb 24–28, 2007: 144LB (abstr). Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346: 2039–46. Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS 2004; 18: 1529–37.
Did the drug cause death? Codeine and breastfeeding See Correspondence page 625
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A breastfeeding mother takes codeine with paracetamol, and her baby dies. Was either drug the cause? Gideon Koren and colleagues blamed maternal codeine ingestion for the death of a 13-day-old breastfed baby.1–3 Postmortem blood contained paracetamol and morphine. The mother’s enzyme genotype was consistent with rapid conversion of codeine (methylmorphine) to morphine,1 and possibly of morphine to active morphine-6-glucuronide (M-6-G) rather than inactive morphine-3-glucuronide (M-3-G).2 By another account, postmortem analysis showed “a blood concentration of codeine associated with toxicity in neonates”.4 Nicholas Bateman and colleagues5 question the interpretation of the drug data, the role of breastmilk, and the conclusion that breastfeeding mothers should perhaps avoid codeine.
Postmortem change in drug concentration6–8 is a “toxicological nightmare”,9 and interpretation is correspondingly difficult. Postmortem blood differs greatly from blood used for drug analysis in life, because of coagulation, sedimentation, haemolysis, contamination, and putrefaction. Drugs are redistributed after death as membranes become permeable and active transport ceases, and can be altered by enzymic or microbial action. There are no studies of postmortem redistribution of drugs in neonates. Morphine can be analysed as free or total drug, and total drug includes M-6-G and M-3-G. Gerostamoulos and Drummer suggested on the basis of average concentrations that significant postmortem redistribution of morphine was unlikely, but individual data show otherwise.10 Free morphine concentrations post www.thelancet.com Vol 372 August 23, 2008
mortem were 0·4–5 times those in paired antemortem samples;10 and those in left ventricular blood 0·2–9 times those in femoral venous blood.11,12 Postmortem hydrolysis increases apparent concentrations of free morphine.13 For paracetamol, antemortem and postmortem concentrations can differ fourfold14 and postmortem concentration in aortic blood can be eight times that in femoral venous blood.15 Postmortem perturbations help to explain the bewildering findings in people who died after overdoses of the combination analgesic coproxamol, in whom there was no correlation between paracetamol and propoxyphene concentrations.16 All we can conclude in this case is that the baby absorbed some drug, but we cannot know how much. The effect of maternal drug on a breastfeeding infant depends on: the maternal plasma concentration; transfer from maternal plasma into milk; feed volume; absorption from the infant’s gut; and pharmacokinetics and pharmacodynamics in the infant.17 Morphine is certainly excreted in breastmilk, but excretion fluctuates widely: in one mother’s milk, morphine concentration varied tenfold.18 Codeine, and morphine metabolites, could also enter milk, but may be unstable. β-glucuronidase, which is present in human milk,19 is likely to hydrolyse morphine (and paracetamol) glucuronides. Serious neonatal sedation has not previously been reported even with morphine concentrations higher than those found in this case,20,21 but the half-lives of morphine22 and paracetamol23 are considerably longer in neonates than in adults. Morphine, paracetamol, and metabolites could therefore potentially accumulate in a sick neonate. Bateman and colleagues argue that opioid poisoning, which depresses consciousness, would have restricted the infant’s milk intake and allowed the baby to recover. This suggestion seems reasonable, although there are rare incomplete reports of codeine causing non-lethal spells of apnoea or bradycardia in breastfeeding neonates.24–26 The postulated adverse reaction is toxic,27 and so associated with supra-therapeutic drug concentrations, but here there is no reliable measurement. Bateman and colleagues argue that the time-course is unexpected, although there are possible explanations. Furthermore, while Koren and colleagues hypothesise that the baby was more susceptible because of increased M-6-G production, analytical evidence is lacking. www.thelancet.com Vol 372 August 23, 2008
Science Photo Library
Comment
This case suggests—but does not prove—that, very rarely, abnormal maternal opioid metabolism, perhaps accompanied by impaired clearance or increased susceptibility in the infant, may make codeine hazardous during breastfeeding. We should certainly avoid the use of codeine when paracetamol alone suffices, and so spare the mother constipation and anxiety. But we cannot reassure her that, if she uses an alternative opioid or a non-steroidal anti-inflammatory drug, her infant will be any safer. Robin E Ferner West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham B18 7QH, UK; and Department of Clinical Pharmacology, University of Birmingham, Birmingham, UK [email protected] I am a member of the Pharmacovigilance Expert Advisory Group that provides advice on adverse drug reactions to the UK Commission on Human Medicines, and I have received fees for medicolegal work. 1
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Koren G, Cairns J, Chitayak D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006; 368: 704. Madadi P, Koren G, Cairns J, et al. Safety of codeine during breastfeeding— fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician 2007; 53: 33–35. Madadi P, Chitayat D, Koren G. Codeine and breastfeeding. Lancet 2008; 372: 626. Ontario Superior Court of Justice. Tariq Jamieson by his estate representative Douglas Jamieson, Rani Jamieson and Douglas Jamieson-vJanssen-Ortho Inc and Johnson & Johnson Corporation. Oct 24, 2007. http://www.cba.org/ClassActions/class_2007/ontario/pdf/2007-04-30_ johnsonandjohnson.pdf (accessed July 12, 2008). Bateman DN, Eddlestone M, Sandilands E. Codeine and breastfeeding. Lancet 2008; 372: 625. Rouzioux JM. Résultats des analyses toxicologiques lors des autopsies médico-légales: intérêt—difficultés d’interprétation. Acta Med Legal Soc 1980; 30: 25–42.
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Pélissier-Alicot AL, Gaulier J-M, Champsaur P, Marquet P. Mechanisms underlying postmortem redistribution of drugs: a review. J Anal Toxicol 2003; 27: 533–44. Ferner RE. Post-mortem clinical pharmacology. Br J Clin Pharmacol 2008; published online May 29. DOI:10.1111/j.1365-2125.2008.03231.x (accessed Aug 14, 2008). Pounder DJ, Jones GR. Post-mortem drug redistribution—a toxicological nightmare. Forensic Sci Int 1990; 45: 253–63. Gerostamoulos J, Drummer OH. Postmortem redistribution of morphine and its metabolites. J Forensic Sci 2000; 45: 843–45. Logan BK, Smirnow D. Postmortem distribution and redistribution of morphine in man. J Forensic Sci 1996; 41: 221–29. Crandall CS, Kerrigan S, Agnero B, LaValley J, Zumwalt R, McKinney PE. The influence of site of collection on postmortem morphine concentrations in heroin overdose victims. J Forensic Sci 2006; 51: 413–20. Skopp G, Potsch L, Klingmann A, Mattern R. Stability of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in fresh blood and plasma and postmortem blood samples. J Anal Toxicol 2001; 25: 2–7. Cook DS, Braithwaite RA, Hale KA. Estimating antemortem drug concentrations from postmortem blood samples: the influence of postmortem redistribution. J Clin Pathol 2000; 53: 282–85. Yonemitsu K, Pounder DJ. Postmortem toxico-kinetics of co-proxamol. Int J Legal Med 1992; 104: 347–53. Dwyer PS, Jones IF. Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination. Hum Toxicol 1984; 3 (suppl): 145S–74S.
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Bennett P. Drugs and human lactation. Amsterdam: Elsevier, 1988: 27–57. 18 Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast-milk and resultant exposure of a nursing infant. J Toxicol-Clin Toxicol 1990; 28: 365–70. 19 Gourley GR, Arend RA. Beta-glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. Lancet 1986; 1: 644–46. 20 Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast-milk and acute neonatal neurobehavior—a preliminary-study. Anesthesiology 1990; 73: 864–69. 21 Baka NE, Bayoumeu F, Boutroy MJ, Laxenaire MC. Colostrum morphine concentrations during post-cesarean intravenous patient-controlled analgesia. Anesth Analg 2002; 94: 184–47. 22 Barrett DA, Barker DP, Rutter N, Pawula M, Shaw PN. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions. Br J Clin Pharmacol 1996; 41: 531–37. 23 Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976; 19: 284–94. 24 Naumburg EG, Meny RG. Breast-milk opioids and neonatal apnea. Am J Dis Child 1988; 142: 11–12. 25 Smith JW. Codeine-induced bradycardia in a breast-fed infant. Clin Res 1982; 30: A259 (abstr). 26 Davis JM, Bhutani VK. Neonatal apnea and maternal codeine use. Pediatric Res 1985; 19: A170 (abstr). 27 Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003; 327: 1222–25.
Declining breast cancer incidence and decreased HRT use Breast cancer is the most common cancer in women worldwide, comprising 23% of all cancers, with more than 1 million new cases per year.1 The main risk factors are related to the female sex hormones with oestrogenic and progestagenic activity either produced within the body or given as hormonal contraceptives or hormonereplacement therapy (HRT). Changes in reproductive factors, use of postmenopausal HRT, mammographic screening, and lifestyle factors associated with affluence have been contributing to the increase in breast cancer witnessed during the past few decades in women aged 50 years or older from developed countries. Karen Canfell and co-workers2 recently examined the association between trends in HRT use and incidence of breast cancer in Australia. In the period after the rapid fall in HRT use beginning in 2001, the researchers found a decline in breast cancer incidence in women aged 50 years or older, but not in those younger than 50 years. Similar trends have been observed in the USA,3,4 New Zealand,5 Canada,6 Germany,7 and France.8 The long-term effect of HRT has been debated for decades. Despite possible adverse effects, HRT became increasingly popular among women in developed countries during the 1990s. Results during the late 1990s from two important studies about possible adverse effects 608
did little to affect the increasing popularity.9,10 However, results from the Women’s Health Initiative’s randomised trial in July, 2002, provoked a rapid fall in sales.11 This study estimated an absolute excess risk of adverse events of 19 per 10 000 person-years of use. Women who used HRT were at increased risk of developing breast cancer, heart disease, stroke, and thrombosis. The researchers recommended that HRT should not be continued or started for primary prevention of coronary heart disease. The incidence of breast cancer has been decreasing in women aged 50 years and older in many developed countries in the past few years, but whether this decline has been caused by the falling prevalence in use of HRT or by a reduction in the prevalence of mammographic screening attendance is controversial. A reduction in the prevalence of mammographic screening results in a reduction in the incidence of breast cancer in the short term, because mammography screening brings forward the diagnosis of breast cancer. To exclude changes in screening, Kerlikowska and co-workers3 restricted analyses to 603 411 women aged 50–69 years, all of whom had been screened from 1997 to 2003, inclusively. Their results suggested that the fall in HRT use was the main contributing factor to the decline in incidence of breast cancer seen in the USA since 2002. www.thelancet.com Vol 372 August 23, 2008
Institute of Infectious and Tropical Diseases, University of Brescia, I-25123 Brescia, Italy (CT); and Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA, USA (IF) [email protected] CT has served as adviser for, or has received lecture fees or grant support from, Abbott, Boehringer, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Pfizer, and Roche. IF has served as adviser for, or has received lecture fees or grant support from, Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, and Tibotec. 1
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Molina JM, Andrade-Villanueva J, Echevarria J, et al, for the CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48-week efficacy and safety results of the CASTLE study. Lancet 2008; 372: 646–55. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Jan 29, 2008. www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. pdf (accessed Aug 1, 2008). Clumeck N, Pozniak A, Raffi F, and the EACS Executive Committee. European AIDS Clinical Society (EACS) guidelines for the clinical management of HIV-infected adults. HIV Med 2008; 9: 65–71. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA 2006; 296: 827–43. Eron J Jr, Yeni P, Gathe J Jr, et al, for the KLEAN study team. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 2006; 368: 476–82. Walmsley S, Ruxrungtham K, Slim J, et al. The Gemini Study: saquinavir (SQV/r) vs lopinavir/r (LPV/r) plus emtricitabine/tenofovir (FTC/TDF) as initial therapy in HIV-1 infected patients. 11th European AIDS Conference/EACS, Madrid, Spain; Oct 24–27, 2007: PS1/4 (abstr). Ortiz R, DeJesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 1389–97. Gathe J, da Silva B, Loutfy M. Study M05-730 primary efficacy results at week 48: phase 3, randomized, open-label study of lopinavir/ritonavir tablets once daily vs twice daily, co-administered with tenofovir df + emitricitabine in ARV-naive HIV-1-infected subjects. 15th Conference on Retrovirus and Opportunistic Infections, Boston, MA, USA; Feb 3–6, 2008: 775 (abstr).
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Rotger M, Taff P, Bleiber G, et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005; 192: 1381–86. Rodríguez-Nóvoa S, Martín-Carbonero L, Barreiro P, et al. Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS 2007; 21: 41–46. Malan N, Krantz E, David N, et al. Efficacy and safety of atazanavir-based therapy in antiretroviral naïve subjects, both with and without ritonavir: 48-week results from AI424-089. 13th Conference on Retrovirus and Opportunistic Infections, Denver, CO, USA; Feb 5–8, 2006: 107LB (abstr). The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349: 1993–2003. Riddler SA, Haubrich R, DiRienzo G, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008; 358: 2095–106. Markowitz M, Nguyen BY, Gotuzzo E, et al, for the Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46: 125–33. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: Week 48 results of the MERIT study. 4th IAS Conference on HIV Pathogenesis and Treatment and Prevention, Sydney, Australia; July 22–25, 2007: WESS104 (abstr). Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naïve patients. 14th Conference on Retrovirus and Opportunistic Infections (CROI), Los Angeles, CA, USA; Feb 24–28, 2007: 144LB (abstr). Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002; 346: 2039–46. Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS 2004; 18: 1529–37.
Did the drug cause death? Codeine and breastfeeding See Correspondence page 625
606
A breastfeeding mother takes codeine with paracetamol, and her baby dies. Was either drug the cause? Gideon Koren and colleagues blamed maternal codeine ingestion for the death of a 13-day-old breastfed baby.1–3 Postmortem blood contained paracetamol and morphine. The mother’s enzyme genotype was consistent with rapid conversion of codeine (methylmorphine) to morphine,1 and possibly of morphine to active morphine-6-glucuronide (M-6-G) rather than inactive morphine-3-glucuronide (M-3-G).2 By another account, postmortem analysis showed “a blood concentration of codeine associated with toxicity in neonates”.4 Nicholas Bateman and colleagues5 question the interpretation of the drug data, the role of breastmilk, and the conclusion that breastfeeding mothers should perhaps avoid codeine.
Postmortem change in drug concentration6–8 is a “toxicological nightmare”,9 and interpretation is correspondingly difficult. Postmortem blood differs greatly from blood used for drug analysis in life, because of coagulation, sedimentation, haemolysis, contamination, and putrefaction. Drugs are redistributed after death as membranes become permeable and active transport ceases, and can be altered by enzymic or microbial action. There are no studies of postmortem redistribution of drugs in neonates. Morphine can be analysed as free or total drug, and total drug includes M-6-G and M-3-G. Gerostamoulos and Drummer suggested on the basis of average concentrations that significant postmortem redistribution of morphine was unlikely, but individual data show otherwise.10 Free morphine concentrations post www.thelancet.com Vol 372 August 23, 2008
mortem were 0·4–5 times those in paired antemortem samples;10 and those in left ventricular blood 0·2–9 times those in femoral venous blood.11,12 Postmortem hydrolysis increases apparent concentrations of free morphine.13 For paracetamol, antemortem and postmortem concentrations can differ fourfold14 and postmortem concentration in aortic blood can be eight times that in femoral venous blood.15 Postmortem perturbations help to explain the bewildering findings in people who died after overdoses of the combination analgesic coproxamol, in whom there was no correlation between paracetamol and propoxyphene concentrations.16 All we can conclude in this case is that the baby absorbed some drug, but we cannot know how much. The effect of maternal drug on a breastfeeding infant depends on: the maternal plasma concentration; transfer from maternal plasma into milk; feed volume; absorption from the infant’s gut; and pharmacokinetics and pharmacodynamics in the infant.17 Morphine is certainly excreted in breastmilk, but excretion fluctuates widely: in one mother’s milk, morphine concentration varied tenfold.18 Codeine, and morphine metabolites, could also enter milk, but may be unstable. β-glucuronidase, which is present in human milk,19 is likely to hydrolyse morphine (and paracetamol) glucuronides. Serious neonatal sedation has not previously been reported even with morphine concentrations higher than those found in this case,20,21 but the half-lives of morphine22 and paracetamol23 are considerably longer in neonates than in adults. Morphine, paracetamol, and metabolites could therefore potentially accumulate in a sick neonate. Bateman and colleagues argue that opioid poisoning, which depresses consciousness, would have restricted the infant’s milk intake and allowed the baby to recover. This suggestion seems reasonable, although there are rare incomplete reports of codeine causing non-lethal spells of apnoea or bradycardia in breastfeeding neonates.24–26 The postulated adverse reaction is toxic,27 and so associated with supra-therapeutic drug concentrations, but here there is no reliable measurement. Bateman and colleagues argue that the time-course is unexpected, although there are possible explanations. Furthermore, while Koren and colleagues hypothesise that the baby was more susceptible because of increased M-6-G production, analytical evidence is lacking. www.thelancet.com Vol 372 August 23, 2008
Science Photo Library
Comment
This case suggests—but does not prove—that, very rarely, abnormal maternal opioid metabolism, perhaps accompanied by impaired clearance or increased susceptibility in the infant, may make codeine hazardous during breastfeeding. We should certainly avoid the use of codeine when paracetamol alone suffices, and so spare the mother constipation and anxiety. But we cannot reassure her that, if she uses an alternative opioid or a non-steroidal anti-inflammatory drug, her infant will be any safer. Robin E Ferner West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham B18 7QH, UK; and Department of Clinical Pharmacology, University of Birmingham, Birmingham, UK [email protected] I am a member of the Pharmacovigilance Expert Advisory Group that provides advice on adverse drug reactions to the UK Commission on Human Medicines, and I have received fees for medicolegal work. 1
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Koren G, Cairns J, Chitayak D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006; 368: 704. Madadi P, Koren G, Cairns J, et al. Safety of codeine during breastfeeding— fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician 2007; 53: 33–35. Madadi P, Chitayat D, Koren G. Codeine and breastfeeding. Lancet 2008; 372: 626. Ontario Superior Court of Justice. Tariq Jamieson by his estate representative Douglas Jamieson, Rani Jamieson and Douglas Jamieson-vJanssen-Ortho Inc and Johnson & Johnson Corporation. Oct 24, 2007. http://www.cba.org/ClassActions/class_2007/ontario/pdf/2007-04-30_ johnsonandjohnson.pdf (accessed July 12, 2008). Bateman DN, Eddlestone M, Sandilands E. Codeine and breastfeeding. Lancet 2008; 372: 625. Rouzioux JM. Résultats des analyses toxicologiques lors des autopsies médico-légales: intérêt—difficultés d’interprétation. Acta Med Legal Soc 1980; 30: 25–42.
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Pélissier-Alicot AL, Gaulier J-M, Champsaur P, Marquet P. Mechanisms underlying postmortem redistribution of drugs: a review. J Anal Toxicol 2003; 27: 533–44. Ferner RE. Post-mortem clinical pharmacology. Br J Clin Pharmacol 2008; published online May 29. DOI:10.1111/j.1365-2125.2008.03231.x (accessed Aug 14, 2008). Pounder DJ, Jones GR. Post-mortem drug redistribution—a toxicological nightmare. Forensic Sci Int 1990; 45: 253–63. Gerostamoulos J, Drummer OH. Postmortem redistribution of morphine and its metabolites. J Forensic Sci 2000; 45: 843–45. Logan BK, Smirnow D. Postmortem distribution and redistribution of morphine in man. J Forensic Sci 1996; 41: 221–29. Crandall CS, Kerrigan S, Agnero B, LaValley J, Zumwalt R, McKinney PE. The influence of site of collection on postmortem morphine concentrations in heroin overdose victims. J Forensic Sci 2006; 51: 413–20. Skopp G, Potsch L, Klingmann A, Mattern R. Stability of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in fresh blood and plasma and postmortem blood samples. J Anal Toxicol 2001; 25: 2–7. Cook DS, Braithwaite RA, Hale KA. Estimating antemortem drug concentrations from postmortem blood samples: the influence of postmortem redistribution. J Clin Pathol 2000; 53: 282–85. Yonemitsu K, Pounder DJ. Postmortem toxico-kinetics of co-proxamol. Int J Legal Med 1992; 104: 347–53. Dwyer PS, Jones IF. Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination. Hum Toxicol 1984; 3 (suppl): 145S–74S.
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Bennett P. Drugs and human lactation. Amsterdam: Elsevier, 1988: 27–57. 18 Robieux I, Koren G, Vandenbergh H, Schneiderman J. Morphine excretion in breast-milk and resultant exposure of a nursing infant. J Toxicol-Clin Toxicol 1990; 28: 365–70. 19 Gourley GR, Arend RA. Beta-glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. Lancet 1986; 1: 644–46. 20 Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast-milk and acute neonatal neurobehavior—a preliminary-study. Anesthesiology 1990; 73: 864–69. 21 Baka NE, Bayoumeu F, Boutroy MJ, Laxenaire MC. Colostrum morphine concentrations during post-cesarean intravenous patient-controlled analgesia. Anesth Analg 2002; 94: 184–47. 22 Barrett DA, Barker DP, Rutter N, Pawula M, Shaw PN. Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions. Br J Clin Pharmacol 1996; 41: 531–37. 23 Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976; 19: 284–94. 24 Naumburg EG, Meny RG. Breast-milk opioids and neonatal apnea. Am J Dis Child 1988; 142: 11–12. 25 Smith JW. Codeine-induced bradycardia in a breast-fed infant. Clin Res 1982; 30: A259 (abstr). 26 Davis JM, Bhutani VK. Neonatal apnea and maternal codeine use. Pediatric Res 1985; 19: A170 (abstr). 27 Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003; 327: 1222–25.
Declining breast cancer incidence and decreased HRT use Breast cancer is the most common cancer in women worldwide, comprising 23% of all cancers, with more than 1 million new cases per year.1 The main risk factors are related to the female sex hormones with oestrogenic and progestagenic activity either produced within the body or given as hormonal contraceptives or hormonereplacement therapy (HRT). Changes in reproductive factors, use of postmenopausal HRT, mammographic screening, and lifestyle factors associated with affluence have been contributing to the increase in breast cancer witnessed during the past few decades in women aged 50 years or older from developed countries. Karen Canfell and co-workers2 recently examined the association between trends in HRT use and incidence of breast cancer in Australia. In the period after the rapid fall in HRT use beginning in 2001, the researchers found a decline in breast cancer incidence in women aged 50 years or older, but not in those younger than 50 years. Similar trends have been observed in the USA,3,4 New Zealand,5 Canada,6 Germany,7 and France.8 The long-term effect of HRT has been debated for decades. Despite possible adverse effects, HRT became increasingly popular among women in developed countries during the 1990s. Results during the late 1990s from two important studies about possible adverse effects 608
did little to affect the increasing popularity.9,10 However, results from the Women’s Health Initiative’s randomised trial in July, 2002, provoked a rapid fall in sales.11 This study estimated an absolute excess risk of adverse events of 19 per 10 000 person-years of use. Women who used HRT were at increased risk of developing breast cancer, heart disease, stroke, and thrombosis. The researchers recommended that HRT should not be continued or started for primary prevention of coronary heart disease. The incidence of breast cancer has been decreasing in women aged 50 years and older in many developed countries in the past few years, but whether this decline has been caused by the falling prevalence in use of HRT or by a reduction in the prevalence of mammographic screening attendance is controversial. A reduction in the prevalence of mammographic screening results in a reduction in the incidence of breast cancer in the short term, because mammography screening brings forward the diagnosis of breast cancer. To exclude changes in screening, Kerlikowska and co-workers3 restricted analyses to 603 411 women aged 50–69 years, all of whom had been screened from 1997 to 2003, inclusively. Their results suggested that the fall in HRT use was the main contributing factor to the decline in incidence of breast cancer seen in the USA since 2002. www.thelancet.com Vol 372 August 23, 2008